The present invention relates to a compound that acts on 5-hydroxytryptamine (5-HT) neurotransmission. More particularly, the present invention relates to a novel phenoxypropylamine compound having selective affinity for and simultaneous antagonistic activity against a 5-hydroxytryptamine 1A (5-HT1A) receptor in the central nervous system, as well as a 5-HT reuptake inhibitory activity, which is useful as a pharmaceutical agent, and to a therapeutic agent for depression and the like, which contains this compound. 5-Hydroxytryptamine (5-HT) is also known as xe2x80x9cserotoninxe2x80x9d.
As a compound having an antagonistic activity against 5-HT1A receptor as well as an inhibitory activity on the reuptake of 5-HT, there are known, for example, 1-(4-indolyloxy)-3-(4-(3,4-methylenedioxyphenyl)piperidino)-2-propanol derivative (EP 0722941), 4-(4-fluorophenyl)-1-((6-(methylamino)indan-1-yl)methyl)piperidine derivative (WO 95/33721), 3,6-dihydro-N-methyl-N-(5-chloro-2-pyridyl)-4-(1-naphthalenyl)-1-(2H)pyridine propanamine derivative (U.S. Pat. No. 5,472,966), 3-(5-chlorobenzo[b]thiophen-3-yl)-5,6-dihydroimidazo[2,1-b]thiazol derivative (WO 97/02269), S-(xe2x88x92)-N-(2-(3-(2-naphthyl)-pyrrolidino)ethyl)-N-(2-pyridyl)cyclohexanecarboxamide derivative (WO 97/40038), (R)-3-(N-cyclopentyl-N-n-propylamino)-8-fluoro-5-(N-methylcarbamoyl)-3,4-dihydro-2H-1-benzopyran derivative (WO 96/33710), 3-(2-(4-methylpiperazin-1-yl)benzylidene)-1,3-dihydroindol-2-one derivative (WO 97/36867), (S)-1-(4-indolyloxy)-3-[4-hydroxy-4-(2-naphthyl)piperidino]-propan-2-ol derivative (WO 97/48698) and the like.
JP-A-62-116557 discloses substituted benzyllactams, such as 2-hydroxy-1-[2-((2-oxo-4-pyrrolidinyl)methyl)phenoxy]-3-(4-diphenylmethyl-piperazin-1-yl)propane and the like, which have a binding ability with a serotonin receptor and a muscarinic acetylcholine receptor, and which can be used for the treatment of senile dementia, Alzheimer""s disease, cerebrovascular dementia and the like.
Various diseases of the central nervous system (e.g., depression, anxiety) are considered to be caused by disorders of noradrenalin (NA) and 5-hydroxytryptamine (5-HT), which are neurotransmitters. Accordingly, augmentation of 5-HTergic neurotransmission is considered to mainly influence depressive mood and anxious, whereas augmentation of noradrenergic neurotransmission is considered to influence retardation in depressive patients. The pharmaceutical agents, such as imipramine, desipramine and the like, which are most frequently used for the treatment of depression, are considered to act on depressive patients by improving neurotransmission of one or both of these NA and 5-HT.
The activity of 5-HT is considered to relate to a number of various types of psychiatric disorders. In addition, 5-HT has been considered to be responsible for various conditions (e.g., eating disorder, gastrointestinal injury, control of cardiovascular system and sexual behavior). However, conventional antidepressants, such as imipramine, desipramine and the like, are defective in that they require 3-4 weeks or even longer time for the expression of an anti-depressive effect, which poses clinical problems.
A combined use of various pharmaceutical agents has been considered in an attempt to accelerate expression of effects of antidepressants or to increase their efficacy (Journal of Clinical Psychiatry, Vol. 57; Suppliment 7; pp 25-31). Therein, a noticeably shortened time for clinical expression of the effect by concurrent use of a selective serotonin (5-HT) reuptake inhibitor (SSRI) and a 5-HT1A antagonist, pindolol, has been reported (Journal of Clinical Psychopharmacology, Vol. 17, No. 6, pp. 446-450). It is known that the amount of 5-HT release in the brain does not increase much by SSRI alone, but when combined with a 5-HT1A antagonist, the amount increases markedly (Neurochemical Research, Vol. 21, No. 5, 1996, pp. 557-562). Under such circumstances, the xe2x80x9c5-HT enhancement hypothesisxe2x80x9d was proposed with regard to the expression of the action of antidepressants by Blier and de Montigny (Trends in Pharmacological Sciences, 1994, vol. 15, pp. 220-226). The 5-HT enhancement hypothesis means that the effector mechanism of antidepressant rests in the enhancement of 5-HT release at a terminal. It is based on the understanding that the conventional antidepressants decrease the 5-HT release by single administration, but increase the 5-HT release and express an anti-depressive effect only when they are administered consecutively. From those mentioned above, it is expected that a drug that promotes 5-HT release in the brain from the first can be a rapid onset antidepressant. In other words, a compound concurrently having a serotonin reuptake inhibitory action and a 5-HT1A antagonistic action is considered to be an antidepressant showing quick expression of an anti-depressive effect, namely, a rapid onset antidepressant.
It is an object of the present invention to find a subgroup of 5-hydroxytryptamine (5-HT) receptor, namely, a compound simultaneously having selective affinity for and antagonistic activity against 5-HT1A receptor in the central nervous system in mammals inclusive of human, which compound also having a 5-HT reuptake inhibitory activity.
It is therefore an object of the present invention to provide a compound that expresses an anti-depressive effect quickly, which is a so-called rapid onset antidepressant, and a compound useful for the treatment of 5-HT mediated diseases in the central nervous system, such as schizophrenia, anxiety neurosis, obsessive-compulsive disorder (OCD), panic disorder, social anxiety disorder, seasonal emotional disorder, Anorexia Nervosa, Bulimia Nervosa, nocturnal enuresis, children""s hyperlocomotion, post-traumatic stress disorder(PTSD), senile dementia, hemicrania, stroke, Alzheimer""s disease, recognition disorder, hypertension, gastrointestinal injury, feeding disorders, premenstrual syndrome (PMS), abnormal body temperature regulation, sexual disorder and pain, as well as for the treatment of abnormality in the cardiovascular system, treatment of drug abuse and the like.
The present inventors have conducted intensive studies, and as a result, found that a novel phenoxypropylamine compound of the formula (I), an optical isomer thereof and a pharmaceutically acceptable salt thereof have selective affinity for and simultaneous antagonistic activity against a 5-hydroxytryptamine 1A (5-HT1A) receptor, as well as 5-HT reuptake inhibitory activity, and can be a useful pharmaceutical agent that meets the above-mentioned objects, which resulted in the completion of the present invention. Moreover, the present inventors have also found novel compounds of the formulas (II) and (III) to be mentioned below, which are the synthetic intermediates for the phenoxypropylamine compound.
Accordingly, the present invention provides the following.
1. A phenoxypropylamine compound of the formula (I) 
wherein each symbol in the formula means as follows:
a bond represented by a solid line and a dotted line shows a double bond or a single bond;
X is a hydrogen atom, a hydroxy group, a C1-C8 alkoxy group, an acyloxy group or an oxo group;
provided that when R1 is a group of the following formula (2), X should not be a hydrogen atom;
R1 is a group of the following formula 
xe2x80x83wherein
Y is O or S,
Ar is optionally substituted aromatic hydrocarbon,
R is optionally substituted aryl group or optionally substituted aromatic heterocyclic group,
R5 is optionally substituted aryl group or optionally substituted aromatic heterocyclic group,
Z is void or xe2x80x94CH2xe2x80x94, and
R6 is hydrogen atom, hydroxy group, acetamido group, carboxyl group, alkoxycarbonyl group, cyano group or C1-C8 alkoxy group;
R3 is a hydrogen atom, a C1-C18 alkyl group or a halogen atom;
V is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or the formula xe2x80x94N(R4)xe2x80x94
wherein R4 is hydrogen atom, C1-C18 alkyl group or optionally substituted aralkyl group;
W is void or xe2x80x94CH2xe2x80x94 or xe2x80x94C(xe2x95x90O)xe2x80x94;
R7 is a C1-C4 hydroxyalkyl group, an acyl group, an optionally substituted saturated or unsaturated heterocyclic group, an optionally substituted fused heterocyclic group, a C1-C4 alkylsulfonyl group or the formula xe2x80x94Qxe2x80x94R9 
wherein
Q is xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90S)xe2x80x94, xe2x80x94CH2xe2x80x94 or xe2x80x94S(xe2x95x90O)2xe2x80x94, and
R9 is a group of the following formula 
xe2x80x83or xe2x80x94NHxe2x80x94NHxe2x80x94R15 
wherein R10 and R11 are each independently hydrogen atom, C1-C18 alkyl group, optionally substituted aryl group, optionally substituted aralkyl group or alkoxy group, R12 is hydrogen atom, optionally substituted aryl group, C1-C18 alkyl group, C1-C8 alkoxy group or acyl group, and R15 is hydrogen atom, phenyl group, C1-C4 alkyl group, C1-C2 halogenated alkyl group, halogen atom, C2-C4 alkenyl group, C1-C4 hydroxyalkyl group, alkoxyalkyl group, alkyloxycarbonyl group, optionally substituted amino group, acetamido group, carboxyl group, acyl group, optionally substituted alkyloxy group, alkylthio group or cyano group;
provided that when R1 is a group of the above formula (2), R7 should not be C1-C4 hydroxyalkyl group or acyl group, and R10 and R11 are not each hydrogen atom at the same time; or
R7 and W in combination may form a ring of the following formula 
xe2x80x83wherein
E is oxygen atom or sulfur atom, and
Qxe2x80x2 is an optionally substituted 4 to 7-membered heterocycle having 1 or 2 hetero atom(s) selected from the group consisting of nitrogen atom and oxygen atom in the ring, in which case V is hydrogen atom; and
Ra, Rb and Rc are each independently a hydrogen atom, a C1-C18 alkyl group, a hydroxy group, a C1-C8 alkoxy group, a halogen atom, an acyl group, a nitro group or an amino group;
provided that when R7 and W are bonded to form a ring of the above formula (14), Ra, Rb and Rc are not each hydroxy group or C1-C8 alkoxy group;
an optically active compound thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
2. The compound of the aforementioned 1, which is represented by the formula (I) 
wherein each symbol in the formula means as follows:
a bond represented by a solid line and a dotted line shows a double bond;
X is a hydrogen atom, a hydroxy group, a C1-C8 alkoxy group, an acyloxy group or an oxo group;
R1 is a group of the following formula 
xe2x80x83wherein
Y is O or S,
Ar is optionally substituted benzene or naphthalene,
R2 is optionally substituted aryl group or optionally substituted aromatic heterocyclic group,
R5 is optionally substituted aryl group or optionally substituted aromatic heterocyclic group,
Z is void or xe2x80x94CH2xe2x80x94, and
R6 is hydrogen atom, hydroxy group, acetamido group, carboxyl group, alkoxycarbonyl group, cyano group or C1-C8 alkoxy group;
R3 is a hydrogen atom, a C1-C18 alkyl group or a halogen atom;
V is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or the formula xe2x80x94N(R4)xe2x80x94
wherein R4 is hydrogen atom, C1-C18 alkyl group or optionally substituted aralkyl group;
W is void or xe2x80x94CH2xe2x80x94 or xe2x80x94C((xe2x95x90O)xe2x80x94;
R7 is a C1-C4 hydroxyalkyl group, an acyl group, an optionally substituted saturated or unsaturated heterocyclic group, an optionally substituted fused heterocyclic group, a C1-C4 alkylsulfonyl group or the formula xe2x80x94Qxe2x80x94R9 
wherein
Q is xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90S)xe2x80x94, xe2x80x94CH2xe2x80x94 or xe2x80x94S(xe2x95x90O)2xe2x80x94, and
R9 is a group of the following formula 
xe2x80x83or xe2x80x94NHxe2x80x94NHxe2x80x94R15 
wherein R10 and R11 are each independently hydrogen atom, C1-C18 alkyl group, optionally substituted aryl group, optionally substituted aralkyl group or alkoxy group, R12 is hydrogen atom, optionally substituted aryl group, C1-C18 alkyl group, C1-C8 alkoxy group or acyl group, and R15 is hydrogen atom, phenyl group, C1-C4 alkyl group, C1-C2 halogenated alkyl group, halogen atom, C2-C4 alkenyl group, C1-C4 hydroxyalkyl group, alkoxyalkyl group, alkyloxycarbonyl group, optionally substituted amino group, acetamido group, carboxyl group, acyl group, optionally substituted alkyloxy group, alkylthio group or cyano group; and
Ra, Rb and Rc are each independently a hydrogen atom, a C1-C18 alkyl group, a hydroxy group, a C1-C8 alkoxy group, a halogen atom, an acyl group, a nitro group or an amino group;
provided that when R1 is a group of the above formula (2), R7 should not be C1-C4 hydroxyalkyl group or acyl group, and R10 and R11 are not each hydrogen atom at the same time;
an optically active compound thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
3. The compound of the aforementioned 2, which is represented by the formula (I) wherein each symbol in the formula means as follows:
a bond represented by a solid line and a dotted line shows a double bond;
X is a hydroxy group;
R1 is a group of the following formula 
xe2x80x83wherein
R5 is optionally substituted phenyl group or naphthyl group,
Z is void, and
R6 is hydrogen atom;
R3 is a hydrogen atom or a C1-C4 alkyl group;
V is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94N(R4)xe2x80x94
wherein R4 is hydrogen atom, C1-C6 alkyl group or optionally substituted aralkyl group;
W is void;
R7 is a group of the following formula 
xe2x80x83or the formula xe2x80x94COxe2x80x94R9 
wherein
R8 is hydrogen atom, phenyl group, C1-C4 alkyl group, C1-C2 halogenated alkyl group, halogen atom, C2-C4 alkenyl group, C1-C4 hydroxyalkyl group, alkoxyalkyl group, alkyloxycarbonyl group, optionally substituted amino group, acetamido group, carboxyl group, acyl group, optionally substituted alkyloxy group, alkylthio group or cyano group, and
R9 is a group of the following formula 
xe2x80x83wherein R10 and R11 are each independently hydrogen atom, C1-C18 alkyl group, optionally substituted aryl group, optionally substituted aralkyl group or alkoxy group, and R12 is hydrogen atom, optionally substituted aryl group, C1-C18 alkyl group, C1-C8 alkoxy group or acyl group; and
Ra, Rb and Rc are each a hydrogen atom;
an optically active compound thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
4. The compound of the aforementioned 2 or 3, which is represented by the formula (Ixe2x80x2) 
wherein each symbol is as in the aforementioned 2, an optically active compound thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
5. The compound of the aforementioned 2, which is selected from the group consisting of
(1) 1-(4-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)-propyloxy)benzo(b)furan-2-ylcarbonyl)pyrrolidine,
(2) 4-(4-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)-propyloxy)benzo(b)furan-2-ylcarbonyl)morpholine,
(4) 4-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)propyloxy)-N,N-dimethylbenzo(b)furan-2-carboxamide,
(12) 1-(4-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)-propyloxy)benzo(b)thiophen-2-ylcarbonyl)pyrrolidine,
(13) 4-(4-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)-propyloxy)benzo(b)thiophen-2-ylcarbonyl)morpholine,
(15) 4-(2-hydroxy-3-(4-(naphthalen-1-yl)piperidino)propyloxy)-N,N-dimethylbenzo(b)thiophene-2-carboxamide,
(17) 4-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)propyloxy)-N,N-dimethylbenzo(b)thiophene-2-carboxamide,
(20) 4-(7-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)-propyloxy)benzo(b)furan-2-ylcarbonyl)morpholine,
(21) 7-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)propyloxy)-N,N-dimethylbenzo(b)furan-2-carboxamide,
(27) 4-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)propyloxy)-N,N-dimethyl-1H-indole-2-carboxamide,
(30) 4-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)propyloxy)-N,N-dimethyl-1-methylindole-2-carboxamide,
(35) 1-(2-(5-methyl-1,2,4-oxadiazol-3-yl)benzo(b)furan-4-yloxy)-3-(4-(naphthalen-2-yl)piperidino)-2-propanol,
(37) 1-(2-(5-methyl-1,3,4-oxadiazol-2-yl)benzo(b)furan-4-yloxy)-3-(4-(naphthalen-2-yl)piperidino)-2-propanol,
(38) 1-(2-(5-trifluoromethyl-1,3,4-oxadiazol-2-yl)benzo(b)furan-4-yloxy)-3-(4-(naphthalen-2-yl)piperidino)-2-propanol,
(39) 1-(2-(5-methyl-1,3,4-oxadiazol-2-yl)benzo(b)furan-7-yloxy)-3-(4-(naphthalen-2-yl)piperidino)-2-propanol,
(42) 1-(2-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-indole-4-yloxy)-3-(4-(naphthalen-2-yl)piperidino)-2-propanol,
(44) 1-(2-(3-methyl-1,2,4-oxadiazol-5-yl)benzo(b)furan-4-yloxy)-3-(4-(naphthalen-2-yl)piperidino)-2-propanol,
(48) 1-(2-(5-methyloxazol-2-yl)benzo(b)furan-7-yloxy)-3-(4-(naphthalen-2-yl)piperidino)-2-propanol,
(81) 3-(4-(3,4-dichlorophenyl)piperidino)-1-(2-(5-methyloxazol-2-yl)benzo(b)furan-4-yloxy)-2-propanol,
(88) 1-(4-(3,4-dichlorophenyl)piperidino)-3-(2-(5-methyl-1,3,4-oxadiazol-2-yl)benzo(b)furan-4-yloxy)-2-propanol, and
(93) 3-(4-(3,4-dimethylphenyl)piperidino)-1-(2-(5-ethyl-1,3,4-oxadiazol-2-yl)benzo(b)furan-4-yloxy)-2-propanol, an optically active compound thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
6. The compound of the aforementioned 1, which is represented by the formula (I) 
wherein each symbol in the formula means as follows:
a bond represented by a solid line and a dotted line shows a double bond or a single bond;
X is a hydrogen atom, a hydroxy group, a C1-C8 alkoxy group or an acyloxy group;
R1 is a group of the following formula 
xe2x80x83wherein
R2 is optionally substituted aryl group or optionally substituted aromatic heterocyclic group,
R5 is optionally substituted aryl group or optionally substituted aromatic heterocyclic group,
Z is void or xe2x80x94CH2xe2x80x94, and
R6 is hydrogen atom, hydroxy group or C1-C8 alkoxy group;
R3 is a hydrogen atom, a C1-C18 alkyl group or a halogen atom;
R7 and W are bonded to form a ring of the following formula 
xe2x80x83wherein
E is an oxygen atom or a sulfur atom, and
Qxe2x80x2 is an optionally substituted 4 to 7-membered heterocycle having 1 or 2 hetero atom(s) selected from the group consisting of nitrogen atom and oxygen atom in the ring, and V is hydrogen atom; and
Ra, Rb and Rc are each independently a hydrogen atom, a C1-C18 alkyl group, a halogen atom, an acyl group, a nitro group or an amino group;
an optically active compound thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
7. The compound of the aforementioned 6, which is represented by the formula (I) wherein each symbol in the formula means as follows:
a group of the following formula 
xe2x80x83is a group of the following formula 
xe2x80x83wherein
E is an oxygen atom or a sulfur atom,
q is 0, 1, 2 or 3,
R4xe2x80x2, R7 and R8xe2x80x2 are each independently a hydrogen atom, a C1-C18 alkyl group, an optionally substituted aryl group or an optionally substituted aralkyl group, and
other symbols are as defined in the aforementioned 6, an optically active compound thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
8. The compound of the aforementioned 6, which is represented by the formula (I) wherein each symbol in the formula means as follows:
a bond represented by a solid line and a dotted line shows a double bond;
X is a hydroxy group;
R1 is a group of the following formula 
xe2x80x83wherein
R5 is optionally substituted phenyl group or naphthyl group,
Z is void, and
R6 is hydrogen atom;
R3 is a hydrogen atom or a C1-C4 alkyl group;
a group of the following formula 
xe2x80x83is a group of the following formula 
xe2x80x83wherein q is 1 and R4xe2x80x2 is hydrogen atom or C1-C4 alkyl group; and
Ra, Rb and Rc are each a hydrogen atom;
an optically active compound thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
9. The compound of the aforementioned 6, which is represented by the formula (Ixe2x80x3) 
wherein each symbol is as defined in the aforementioned 6, an optically active compound thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
10. The compound of the aforementioned 6, which is selected from the group consisting of
(306) 5-(2xe2x80x2-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)-propyloxy)benzylidene)-1,3-dimethylimidazolidine-2,4-dione,
(307) xcex1-(2xe2x80x2-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)-propyloxy) benzylidene)-xcex3-butyrolactone,
(309) xcex1-(2xe2x80x2-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)-propyloxy)benzylidene)-xcex3-butyrolactone,
(310) xcex1-(2xe2x80x2-(3-(4-(3-fluoro-4-methylphenyl)piperidino)-2-hydroxypropyloxy)benzylidene)-xcex3-butyrolactone,
(311) xcex1-(2xe2x80x2-(3-(4-(3,4-dimethylphenyl)piperidino)-2-hydroxypropyloxy)benzylidene)-xcex3-butyrolactone,
(312) xcex1-(2xe2x80x2-(3-(4-(4-chloro-3-fluorophenyl)piperidino)-2-hydroxypropyloxy)benzylidene)-xcex3-butyrolactone,
(313) xcex1-(2xe2x80x2-(3-(4-(4-chloro-3-trifluoromethylphenyl)-piperidino)-2-hydroxypropyloxy) benzylidene)-xcex3-butyrolactone,
(314) xcex1-(2xe2x80x2-(2-hydroxy-3-(4-(naphthalen-1-yl)piperidino)-propyloxy) benzylidene)-xcex3-butyrolactone,
(315) xcex1-(2xe2x80x2-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)-propyloxy)benzylidene)-xcex4-valerolactone,
(316) xcex1-(2xe2x80x2-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)-propyloxy) benzylidene)-xcex3-valerolactone,
(319) 3-(2xe2x80x2-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)-propyloxy)benzylidene)-2-pyrrolidone,
(322) 3-(2xe2x80x2-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)-propyloxy)benzylidene)-1-methyl-2-pyrrolidone, and
(325) xcex1-(2xe2x80x2-(2-hydroxy-3-(4-(6-methoxynaphthalen-2-yl) piperidino)propyloxy)benzylidene)-xcex3-butyrolactone, an optically active compound thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
11. A pharmaceutical agent comprising a compound of the aforementioned 1, an optically active compound thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
12. The pharmaceutical agent of the aforementioned 11, which is an agent for the treatment of depression.
13. A pharmaceutical composition comprising at least one member selected from the group consisting of a compound of the aforementioned 1, an optically active compound thereof, a pharmaceutically acceptable salt thereof and a hydrate thereof, and a pharmaceutically acceptable carrier.
14. The pharmaceutical composition of the aforementioned 13, which is an agent for the treatment of depression.
15. A 5HT1A antagonist having a selective serotonin reuptake inhibitory action, which comprises a compound of the aforementioned 1, an optically active compound thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
16. A selective serotonin reuptake inhibitor having a 5HT1A antagonistic action, which comprises a compound of the aforementioned 1, an optically active compound thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
17. A compound of the formula (II) 
wherein each symbol in the formula means as follows:
X is a hydrogen atom, a hydroxy group, a C1-C8 alkoxy group or an acyloxy group or an oxo group;
R1 is a group of the following formula 
xe2x80x83wherein
Y is O or S,
Ar is optionally substituted benzene or naphthalene,
R2 is optionally substituted aryl group or optionally substituted aromatic heterocyclic group,
R5 is optionally substituted aryl group or optionally substituted aromatic heterocyclic group,
Z is void or xe2x80x94CH2xe2x80x94, and
R6 is hydrogen atom, hydroxy group, acetamido group, carboxyl group, alkoxycarbonyl group, cyano group or C1-C8 alkoxy group, provided that when V is xe2x80x94N(R4)xe2x80x94, R6 should not be hydroxy group;
R3 is a hydrogen atom, a C1-C18 alkyl group or a halogen atom;
V is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or the formula xe2x80x94N(R4)xe2x80x94
wherein
R4 is hydrogen atom, C1-C18 alkyl group or optionally substituted aralkyl group;
W is void, xe2x80x94CH2xe2x80x94 or xe2x80x94C(xe2x95x90O)xe2x80x94;
R14 is a hydrogen atom or a C1-C4 alkyl; and
Ra, Rb and Rc are each independently a hydrogen atom, a C1-C18 alkyl group, a hydroxy group, a C1-C8 alkoxy group, a halogen atom, an acyl group, a nitro group or an amino group;
an optically active compound thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
18. A compound of the formula (III) 
wherein each symbol is as follows:
R is an allyl group or a 2,3-epoxypropan-1-yl group;
a bond represented by a solid line and a dotted line shows a double bond or a single bond;
E is an oxygen atom or a sulfur atom;
R3 is a hydrogen atom, a C1-C18 alkyl group or a halogen atom;
Qxe2x80x2 is an optionally substituted 4 to 7-membered heterocycle having 1 or 2 hetero atom(s) selected from the group consisting of nitrogen atom and oxygen atom in the ring; and
Ra, Rb and Rc are each independently a hydrogen atom, a C1-C18 alkyl group, a hydroxy group, a C1-C8 alkoxy group, a halogen atom, an acyl group, a nitro group or an amino group;
an optically active compound thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
19. The compound of the aforementioned 18, wherein, in the formula (III), each symbol is as follows:
the group of the following formula 
xe2x80x83is a group of the following formula 
xe2x80x83wherein
E is oxygen atom or sulfur atom,
q is 0, 1, 2 or 3,
R4xe2x80x2, R7 and R8xe2x80x2 are each independently hydrogen atom, C1-C18 alkyl group, optionally substituted aryl group or optionally substituted aralkyl group, and
other symbols are as defined in the aforementioned 18, an optically active compound thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
20. A compound selected from the group consisting of
2-(4-methoxybenzo(b)furan-2-yl)-5-methyl-1,3,4-oxadiazole,
2-(4-hydroxybenzo(b)furan-2-yl)-5-methyl-1,3,4-oxadiazole,
(S)-2-(4-glycidyloxybenzo(b)furan-2-yl)-5-methyl-1,3,4-oxadiazole,
2-(7-methoxybenzo(b)furan-2-yl)-5-methyl-1,3,4-oxadiazole,
2-(4-(methoxymethyloxy)benzo(b)thiophen-2-yl)-5-methyl-1,3,4-oxadiazole,
2-(4-hydroxybenzo(b)thiophen-2-yl)-5-methyl-1,3,4-oxadiazole,
4-benzyloxy-2-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-indole,
2-(7-methoxybenzo(b)furan-2-yl)-5-phenyl-1,3,4-oxadiazole,
2-(4-methoxybenzo(b)furan-2-yl)-5-trifluoromethyl-1,3,4-oxadiazole,
2-(4-hydroxybenzo(b)furan-2-yl)-5-trifluoromethyl-1,3,4-oxadiazole,
(S)-2-(4-glycidyloxybenzo(b)furan-2-yl)-5-trifluoromethyl-1,3,4-oxadiazole,
2-(7-methoxybenzo(b)furan-2-yl)-5-trifluoromethyl-1,3,4-oxadiazole,
2-(7-hydroxybenzo(b)furan-2-yl)-5-trifluoromethyl-1,3,4-oxadiazole,
(S)-2-(7-glycidyloxybenzo(b)furan-2-yl)-5-trifluoromethyl-1,3,4-oxadiazole,
Nxe2x80x2-(4-methoxybenzo(b)furan-2-ylcarbonyl)propionohydrazide,
2-(4-methoxybenzo(b)furan-2-yl)-5-ethyl-1,3,4-oxadiazole,
2-(4-hydroxybenzo(b)furan-2-yl)-5-ethyl-1,3,4-oxadiazole,
(S)-2-(4-glycidyloxybenzo (b) furan-2-yl)-5-ethyl-1,3,4-oxadiazole,
2-(4-methoxybenzo(b)furan-2-yl)-5-methyl-1,3,4-thiadiazole,
2-(4-hydroxybenzo(b)furan-2-yl)-5-methyl-1,3,4-thiadiazole,
(S)-2-(4-glycidyloxybenzo(b)furan-2-yl)-5-methyl-1,3,4-thiadiazole,
5-ethoxycarbonyl-2-(4-methoxybenzo(b)furan-2-yl)-1,3,4-oxadiazole,
5-ethoxycarbonyl-2-(4-hydroxybenzo(b)furan-2-yl)-1,3,4-oxadiazole,
5-(4-(methoxymethyloxy)benzo(b)furan-2-yl)-2,3-dihydro-1,3,4-oxadiazole-2-thione,
5-(4-(methoxymethyloxy) benzo (b)furan-2-yl)-2-methylthio-1,3,4-oxadiazole,
5-(4-hydroxybenzo(b)furan-2-yl)-2-methylthio-1,3,4-oxadiazole,
5-(4-(methoxymethyloxy)benzo(b)furan-2-yl)-2,3-dihydro-1,3,4-oxadiazol-2-one,
5-(4-(methoxymethyloxy)benzo(b)furan-2-yl)-2-methoxy-1,3,4-oxadiazole,
(S)-5-(4-glycidyloxybenzo(b)furan-2-yl)-2-methoxy-1,3,4-oxadiazole,
2-ethoxy-5-(4-(methoxymethyloxy)benzo(b)furan-2-yl)-1,3,4-oxadiazole,
(S)-2-ethoxy-5-(4-glycidyloxybenzo(b)furan-2-yl)-1,3,4-oxadiazole,
2-(1-methylethyloxy)-5-(4-(methoxymethyloxy)benzo(b)furan-2-yl)-1,3,4-oxadiazole and
(S)-2-(1-methylethyloxy)-5-(4-glycidyloxybenzo(b)furan-2-yl)-1,3,4-oxadiazole.
The definitions and examples of each group in the formulas (I), (Ixe2x80x2), (Ixe2x80x3), (II) and (III) are shown in the following.
The acyloxy group at X is, for example, acetoxy, propionyloxy, butyryloxy, benzoyloxy and the like, preferably acetoxy.
The xe2x80x9caryl groupxe2x80x9d of the optionally substituted aryl group at Ar, R2, R5, R10, R11, R12, R4xe2x80x2, R7xe2x80x2 and R8xe2x80x2 is, for example, phenyl, naphthyl, tetrahydronaphthyl (e.g., 1,2,3,4-tetrahydronaphthalene-6-yl, 5,6,7,8-tetrahydronaphthalen-2-yl etc.), indanyl (e.g., indan-5-yl etc.), indenyl (e.g., inden-5-yl etc.) and the like, with preference given to phenyl and naphthyl. These may be substituted by one or more, the same or different substituents mentioned below. A hydrogen atom may be added to the double bond of these aryl groups. Examples of the xe2x80x9csubstituentxe2x80x9d include halogen atom (e.g., chlorine atom, fluorine atom etc.), trifluoromethyl, C1-C4 alkyl group (linear or branched chain, such as methyl, ethyl, propyl, isopropyl, butyl etc.), C1-C4 alkoxy group (linear or branched chain, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy etc.), aryl group (e.g., phenyl etc.), aralkyl group (e.g., benzyl etc.), oxo group, alkoxyalkyl group (e.g., methoxyethyl etc.) and the like, with preference given to chlorine atom, fluorine atom, trifluoromethyl, methyl, methoxy, phenyl, benzyl, oxo, methoxyethyl and the like.
Preferable examples of the optionally substituted aryl group at R5 include naphthyl (1-naphthyl, 2-naphthyl), 4-chloro-3-fluorophenyl, 3-chloro-4-trifluoromethylphenyl, 3,4-dimethylphenyl, 3,4-dichlorophenyl, 2,4- or 3,4-dimethylphenyl, 4-methylphenyl, 4-fluorophenyl, 3-chloro-4-methylphenyl, 4-chloro-3-trifluoromethylphenyl, 6-methoxynaphthyl-2-yl, 4-chlorophenyl, 3,4-difluorophenyl, 3,4-dimethoxyphenyl, 3-chlorophenyl, 4-chloro-3-methylphenyl, 4-chloro-3-methoxyphenyl, 2,5-dichlorophenyl, 4-chloro-3-trifluorophenyl and the like.
Examples of the xe2x80x9caromatic hydrocarbonxe2x80x9d of the optionally substituted aromatic hydrocarbon at Ar include benzene, naphthalene and the like, which may be substituted by one or more, the same or different substituents mentioned below. The xe2x80x9csubstituentxe2x80x9d is, for example, halogen atom (e.g., chlorine atom, fluorine atom etc.), trifluoromethyl, C1-C4 alkyl group (linear or branched chain, such as methyl, ethyl, propyl, isopropyl, butyl etc.), C1-C4 alkoxy group (linear or branched chain, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy etc.), aryl group (e.g., phenyl etc.), aralkyl group (e.g., benzyl etc.), oxo group, alkoxyalkyl group (e.g., methoxyethyl etc.) and the like, with preference given to chlorine atom, fluorine atom, trifluoromethyl, methyl, methoxy, phenyl, benzyl, oxo group, methoxyethyl and the like.
The xe2x80x9caromatic heterocyclic groupxe2x80x9d of the optionally substituted aromatic heterocyclic group at R2 and R5 is, for example, pyridyl, furyl, thienyl, pyrimidinyl, indolyl (e.g., indol-2-yl, indol-6-yl, indol-5-yl etc.), benzo(b)thienyl (e.g., benzo(b)thiophen-2-yl, benzo(b)thiophen-5-yl, 2,3-dihydrobenzo(b)thiophen-6-yl, 2,3-dihydrobenzo(b)thiophen-5-yl etc.), benzo(b)furyl (e.g., benzo(b)furan-2-yl, benzo(b)furan-5-yl, benzo(b)furan-6-yl, 2,3-dihydrobenzo(b)furan-5-yl, 2,3-dihydrobenzo(b)furan-4-yl, 3,4-dihydro-2H-benzo(b)furan-6-yl, 2,3-dihydrobenzo(b)furan-6-yl etc.), 3,4-methylenedioxyphenyl, benzimidazolyl (e.g., 2,3-dihydrobenzimidazol-1-yl etc.), 1,4-benzodioxanyl (e.g., 1,4-benzodioxan-6-yl etc.), chromanyl (e.g., chroman-6-yl, chroman-7-yl etc.), indolinyl (e.g., indolin-5-yl etc.), chromenyl (e.g., 2H-chromen-6-yl, 2H-chromen-7-yl etc.), benzo(b)thiinyl (e.g., 3,4-dihydro-2H-benzo(b)thiin-7-yl, 3,4-dihydro-2H-benzo(b)thiin-6-yl etc.), benzoisoxazolyl (e.g., benzoisoxazol-5-yl, benzo(d)isoxazol-5-yl etc.), benzo(c)furyl (e.g., 1,3-dihydrobenzo(c)furan-5-yl etc.), isochromanyl (e.g., isochroman-7-yl, isochroman-6-yl etc.), quinolinyl (e.g., quinolin-3-yl, quinolin-6-yl etc.), 3,4-dihydro-2H-benzo(b)oxin-6-yl, 3,4-dihydro-2H-benzo(c)oxin-6-yl, isoindolinyl (e.g., isoindolin-5-yl etc.), isoquinolinyl (e.g., isoquinolin-6-yl etc.) and the like, which may be substituted by one to three the same or different substituents mentioned below.
Examples of the xe2x80x9csubstituentxe2x80x9d include halogen atom (e.g., fluorine atom, chlorine atom, bromine atom etc.), haloalkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl etc.), C1-C4 alkyl (linear or branched chain, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl etc.), C1-C8 alkoxy group (linear or branched chain, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy etc.), hydroxy, nitro, cyano, amino, mono or dialkylamino wherein each alkyl has 1 to 4 carbon atoms (e.g., methylamino, dimethylamino, diethylamino, dipropylamino etc.), acyl (e.g., acetyl, propionyl, butyryl etc.), C2-C6 alkenyl (e.g., vinyl, 1-propenyl, 2-propenyl, 3-propenyl etc.), C2-C6 alkynyl (e.g., ethynyl, 1-propynyl, 2-propynyl etc.), phenyl, phenoxy, benzyloxy, Rxe2x80x2-S(O)t- wherein Rxe2x80x2 is C1-C4 alkyl and t is 0, 1 or 2, Ph-S(O)t- wherein Ph is phenyl and t is as defined above, carbamoyl, N,N-dialkylcarbamoyl (e.g., N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N,N-dipropylcarbamoyl etc.), oxo and the like, with preference given to C1-C4 alkyl.
The C1-C8 alkoxy group at X, R6, R12, Ra, Rb and Rc is linear or branched chain, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and the like, with preference given to C1-C4 alkoxy, with particular preference given to methoxy.
The halogen atom at R3, Ra, Rb and Rc is fluorine atom, chlorine atom, bromine atom or iodine atom, preferably fluorine atom and chlorine atom.
The C1-C18 alkyl group at R3, R4, R10 R11, R12 Ra Rb Rc R4xe2x80x2, R7xe2x80x2 and R8xe2x80x2 is linear or branched chain, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, decyl, hexadecyl, octadecyl and the like. Preferably, it is C1-C4 alkyl group at R3 R10, R11, R12 Ra, Rb, Rc, R4xe2x80x2, R7xe2x80x2, R8xe2x80x2, and C1-C6 alkyl group at R4. Particularly preferably, it is methyl, ethyl or isobutyl.
The C1-C4 alkyl group at R8 and R15 is linear or branched chain, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and the like, with preference given to methyl, ethyl and isopropyl.
The acyl group at R7, R12, Ra, Rb and Rc is, for example, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, benzoyl and the like, particularly preferably C2-C3 acyl group (e.g., acetyl).
The xe2x80x9caralkyl groupxe2x80x9d of the optionally substituted aralkyl group at R4, R10, R11, R4xe2x80x2, R7xe2x80x2 and R8xe2x80x2 is a group wherein C1-C4 linear or branched chain alkyl is substituted by phenyl group. Examples thereof include benzyl, 2-phenylethyl, 1-phenylethyl, 1,1-dimethyl-2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-phenylpropyl, 4-phenylbutyl, 3-phenylbutyl, 2-phenylbutyl, 1-phenylbutyl and the like, with preference given to benzyl, which may be substituted by one or more, the same or different substituents mentioned below. Examples of these substituents include halogen atom (e.g., fluorine atom, chlorine atom, bromine atom etc.), haloalkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl etc.), C1-C4 alkyl (linear or branched, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl etc.), C1-C8 alkoxy (linear or branched, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy etc.), hydroxy, nitro, cyano, amino and the like. The optionally substituted aralkyl at R4xe2x80x2, R7xe2x80x2 and R8xe2x80x2 is, for example, benzyl, 2-phenylethyl, 1-phenylethyl, 1,1-dimethyl-2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-phenylpropyl, 4-phenylbutyl, 3-phenylbutyl, 2-phenylbutyl, 1-phenylbutyl and the like, with preference given to benzyl.
The C1-C2 halogenated alkyl group at R8 and R15 is, for example, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl and the like, preferably trichloromethyl and trifluoromethyl.
The halogen atom at R8 and R15 is fluorine atom, chlorine atom, bromine atom or iodine atom, preferably fluorine atom and chlorine atom.
The C2-C4 alkenyl group at R8 and R15 is linear or branched chain, such as vinyl, 1-propenyl, allyl, 1-butenyl, 2-butenyl, isopropenyl and the like, with preference given to vinyl, 1-propenyl and isopropenyl.
The C1-C4 hydroxyalkyl group at R8 and R15 is, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 1-hydroxy-1-methylethyl, 2-hydroxy-1-methylethyl, 1,2-dihydroxy-1-methylethyl and the like, with preference given to hydroxymethyl.
In the alkoxyalkyl group at R8 and R15, the xe2x80x9calkoxyxe2x80x9d moiety is preferably C1-C4 linear or branched chain alkoxy and the xe2x80x9calkylxe2x80x9d moiety is preferably C1-C4 linear or branched chain alkyl. Examples thereof include methoxymethyl, ethoxymethyl, propyloxymethyl, methoxyethyl, ethoxyethyl and the like, with preference given to methoxymethyl.
In the alkyloxycarbonyl group at R8 and R15, the xe2x80x9calkyloxyxe2x80x9d moiety is preferably C1-C4 linear or branched chain alkyloxy, such as methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, butyloxycarbonyl and the like, with preference given to methoxycarbonyl and ethoxycarbonyl.
The optionally substituted amino group at R8 and R15 is preferably amino optionally substituted by one or two, the same or different C1-C2 alkyl. Examples thereof include amino, methylamino, dimethylamino, ethylamino, diethylamino and the like, with preference given to methylamino and dimethylamino.
The acyl group at R8 and R15 is, for example, acetyl, propionyl, butyryl, isobutyryl and the like, with preference given to acetyl.
The optionally substituted alkyloxy group at R8 and R15 is preferably, C1-C4 linear or branched chain, which may be substituted by one or more, the same or different substituents mentioned below. Examples of these xe2x80x9csubstituentsxe2x80x9d include fluorine atom, chlorine atom and the like. Specific examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butyloxy, trifluoromethoxy, 2,2,2-trifluoroethyloxy and the like, with preference given to methoxy and 2,2,2-trifluoroethyloxy.
The alkylthio group at R8 and R15 is preferably C1-C4 linear or branched chain, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio and the like, with preference given to methylthio and ethylthio.
The C1-C4 hydroxyalkyl group at R7 is linear or branched chain, such as 1-hydroxymethyl, 1-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 1-hydroxybutyl and the like, with preference given to 1-hydroxyethyl.
The C1-C4 alkylsulfonyl group at R7 is linear or branched chain, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl and the like, with preference given to ethylsulfonyl.
The optionally substituted saturated or unsaturated heterocyclic group at R7 is a 5 or 6-membered heterocyclic group optionally containing 1-3 hetero atom(s) selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom, such as a group derived from furan, thiophene, pyrrole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, imidazole, furazan, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, oxazoline, thiazoline, imidazoline, tetrahydrofuran, tetrahydrothiophene, pyran and the like. Preferred are groups derived from thiophene, pyrazole, oxazole, isoxazole, thiazole, imidazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,3,4-oxadiazole and the like and more preferred are groups derived from oxazole, thiazole, 1,3,4-thiadiazole, 1,3,4-oxadiazole and the like. These may be substituted by one or two the same or different substituents mentioned below.
Examples of these substituents include optionally substituted aryl group (e.g., phenyl or naphthyl optionally substituted by halogen atom, amino, nitro, hydroxy, C1-C4 alkyl, C1-C4 alkoxy and the like), C1-C18 alkyl group (as defined above, preferably methyl, ethyl, isopropyl, tert-butyl, isobutyl etc.), C1-C2 halogenated alkyl group (as defined above), C1-C8 alkoxy group (as defined above, preferably methoxy, ethoxy, isopropyloxy etc.), halogen atom (e.g., fluorine atom, chlorine atom, bromine atom or iodine atom), C2-C4 alkenyl group (e.g., vinyl, 1-propenyl, allyl, 1-butenyl, 2-butenyl, isopropenyl etc.), C1-C4 hydroxyalkyl group (e.g., hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl etc.), alkoxyalkyl group (e.g., methoxymethyl, ethoxymethyl, propyloxymethyl, methoxyethyl, ethoxyethyl etc.), alkyloxycarbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, butyloxycarbonyl etc.), optionally substituted amino group (e.g., amino, methylamino, dimethylamino, ethylamino, diethylamino etc.), acyl group (e.g., acetyl, propionyl, butyryl, isobutyryl etc.), acetamido group, carboxyl group, optionally substituted alkyloxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy, butyloxy, trifluoromethoxy, 2,2,2-trifluoromethoxy etc.), alkylthio group (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio etc.), cyano group and the like.
Examples of the optionally substituted fused heterocyclic group at R7 include groups derived from benzofuran, benzothiophene, indole, benzoxazole, benzothiazole, 1,2-benzoisoxazole, 1,2-benzoisothiazole, benzimidazoline and the like, with preference given to benzoxazol-2-yl and benzothiazol-2-yl. These may be substituted by one or more, the same or different substituents mentioned below. Examples of these substituents include halogen atom (e.g., fluorine atom, chlorine atom, bromine atom etc.), haloalkyl group (e.g., fluoromethyl, difluoromethyl, trifluoromethyl etc.), C1-C4 alkyl group (linear or branched, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl etc.), C1-C8 alkoxy group (linear or branched, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy etc.), hydroxy group, nitro group, cyano group, amino group and the like.
The alkoxycarbonyl group at R6 is preferably C1-C4 linear or branched chain, such as ethoxycarbonyl, methoxycarbonyl, propoxycarbonyl, butoxycarbonyl and the like, with preference given to ethoxycarbonyl.
The C1-C4 alkyl group at R14 is linear or branched, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like, with preference given to methyl and ethyl.
The alkoxy group at R10 and R11 is, for example, linear or branched chain alkoxy having 1 to 4, preferably 1 or 2, carbon atoms, such as methoxy, ethoxy and the like, with preference given to methoxy.
The xe2x80x9ccycloalkylene groupxe2x80x9d of the optionally substituted C3-C8 cycloalkylene group at Yxe2x80x2 is, for example, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cycloctylene and the like. Examples of the substituent include C1-C4 alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl etc.), C1-C8 alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy etc.), hydroxy group, oxo group and the like. Examples of the optionally substituted C3-C8 cycloalkylene include 2-methoxycyclopentylene, 2-methylcyclohexylene, 2,6-dimethylcyclohexylene, 3-ethylcycloheptylene, 3-hydroxycycloheptylene and the like, with preference given to 2,6-dimethylcyclohexylene.
The C1-C8 alkylene group at Yxe2x80x2 is, for example, linear or branched, such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, methylmethylene, dimethylmethylene, 1-methylethylene, 2-methylethylene, 1,1-dimethylethylene, 2,2-dimethylethylene, ethylmethylene, diethylmethylene, 1-ethylethylene, 2-ethylethylene, 1-methyltrimethylene, 1,1-dimethyltrimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 3-methyltrimethylene, 3,3-dimethyltrimethylene, 1-ethyltrimethylene, 2-ethyltrimethylene, 3-ethyltrimethylene and the like, with preference given to ethylene, trimethylene and tetramethylene.
The C1-C4 alkyleneoxy group at Yxe2x80x2 is, for example, linear or branched, such as methyleneoxy, ethyleneoxy, trimethyleneoxy, tetramethyleneoxy, methylmethyleneoxy, dimethylmethyleneoxy, 1-methylethyleneoxy, 2-methylethyleneoxy, 1,1-dimethylethyleneoxy, 2,2-dimethylethyleneoxy, ethylmethyleneoxy, 1-ethylethyleneoxy, 2-ethylethyleneoxy, 1-methyltrimethyleneoxy, 2-methyltrimethyleneoxy, 3-methyltrimethyleneoxy and the like, with preference given to ethyleneoxy. The alkyleneoxy group here means both xe2x80x94ROxe2x80x94 and xe2x80x94ORxe2x80x94, wherein R is C1-C4 alkylene. For example, ethyleneoxy means both xe2x80x94CH2CH2Oxe2x80x94 and xe2x80x94OCH2CH2xe2x80x94.
The optionally substituted 4 to 7-membered heterocycle having 1 or 2 hetero atom(s) selected from the group consisting of nitrogen atom and oxygen atom in the ring at Qxe2x80x2 is, for example, a group derived from 3,5-dihydroimidazole, imidazolidine, pyrrolidine, oxazolidine, oxetane, oxolane, oxane, perhydroazepine, imidazolidine, oxepane, azetidine and the like. Examples of these substituents include C1-C18 alkyl group (e.g., methyl, ethyl etc.), C2-C4 alkoxyalkyl group (e.g., 2-methoxyethyl etc.), optionally substituted aryl group (as defined above, e.g., phenyl etc.), optionally substituted aralkyl group (as defined above, e.g., benzyl etc.), oxo group, thioxo group and the like. Preferable examples of the heterocycle group include groups derived from 3,5-dihydro-2-methylimidazole, 3,5-dihydro-2,3-dimethylimidazole, 3,5-dihydro-2-methyl-3-phenylimidazole, 3,5-dihydro-3-ethyl-2-methylimidazole, 3-benzyl-3,5-dihydro-2-methylimidazole, 1,3-dimethylimidazolidine, pyrrolidine, 1-methylpyrrolidine, 1-(2-methoxyethyl)pyrrolidine, oxazolidine and 5,5-dimethyloxane.
The C1-C4 alkyl group at R is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and the like, with preference given to methyl and ethyl.
Examples of the X include hydrogen atom, hydroxy, methoxy, ethoxy, isopropoxy, acetoxy and the like, with particular preference given to hydroxy.
As R1, a group of the following formula is preferable: 
wherein R5 is optionally substituted phenyl group or naphthyl group, Z is void and R6 is hydrogen atom.
Specific examples of R1 include
1-benzylpiperidin-4-ylamino,
4-phenylcyclohexyl-1-ylamino,
4-hydroxy-4-(4-chlorophenyl)piperidino,
4-hydroxy-4-(2-naphthyl)piperidino,
4-hydroxy-4-(benzo(b)thiophen-2-yl)piperidino,
4-benzylpiperidino,
4-(4-fluorobenzyl)piperidino,
4-(4-chlorobenzyl)piperidino,
4-(4-bromobenzyl)piperidino,
4-phenylpiperidino,
4-(4-fluorophenyl)piperidino,
4-(4-chlorophenyl)piperidino,
4-(4-bromophenyl)piperidino,
4-(4-methoxyphenyl)piperidino,
4-(4-methylphenyl)piperidino,
4-(4-trifluoromethylphenyl)piperidino,
4-(3-chlorophenyl)piperidino,
4-(3-fluorophenyl)piperidino,
4-(3-trifluoromethylphenyl)piperidino,
4-(3-bromophenyl) piperidino,
4-(3-methoxyphenyl)piperidino,
4-(3-methylphenyl)piperidino,
4-(2-fluorophenyl) piperidino,
4-(2-chlorophenyl) piperidino,
4-(2-bromophenyl)piperidino,
4-(2-methylphenyl)piperidino,
4-(2-methoxyphenyl)piperidino,
4-(3,4-dichlorophenyl)piperidino,
4-(3,4-dimethylphenyl)piperidino,
4-(3,4-dimethoxyphenyl)piperidino,
4-(3,4-methylenedioxyphenyl)piperidino,
4-(2,3-dimethoxyphenyl)piperidino,
4-(2,3-dimethylphenyl)piperidino,
4-(2,3-dichlorophenyl)piperidino,
4-(3,5-dimetheoxyphenyl)piperidino,
4-(3,5-dimethylphenyl)piperidino,
4-(3,5-dichlorophenyl)piperidino,
4-(2,6-dimethoxyphenyl)piperidino,
4-(3,4,5-trimethoxyphenyl)piperidino,
4-(naphthalen-1-yl)piperidino,
4-(naphthalen-2-yl)piperidino,
4-(6-methoxynaphthalen-2-yl)piperidino,
4-(benzo(b)thiopyhen-2-yl)piperidino,
4-(benzo(b)furan-2-yl)piperidino,
4-(indol-2-yl)piperidino,
4-(4-fluorobenzyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(4-chlorobenzyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(4-bromobenzyl)-3,6-dihydro-2H-pyridin-1-yl,
4-phenyl-3,6-dihydro-2H-pyridin-1-yl,
4-(4-fluorophenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(4-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(4-bromophenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(4-methoxyphenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(4-methylphenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(4-trifluoromethylphenyl)-36-dihydro-2H-pyridin-1-yl,
4-(3-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(3-fluorophenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(3-bromophenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(3-methoxyphenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(3-methylphenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(2-fluorophenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(2-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(2-bromophenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(2-methylphenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(2-methoxyphenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(3,4-dichlorophenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(3,4-dimethylphenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(3,4-dimethoxyphenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(3,4-methylenedioxyphenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(2,3-dimethoxyphenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(2,3-dimethylphenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(2,3-dichlorophenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(3,5-dimethoxyphenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(3,5-dimethylphenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(3,5-dichlorophenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(2,6-dimethoxyphenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(3,4,5-trimethoxyphenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(naphthalen-1-yl)-3,6-dihydro-2H-pyridin-1-yl,
4-(naphthalen-2-yl)-3,6-dihydro-2H-pyridin-1-yl,
4-(6-methoxynaphthalen-2-yl)-3,6-dihydro-2H-pyridin-1-yl,
4-(benzo(b)thiophen-2-yl)-3,6-dihydro-2H-pyridin-1-yl,
4-(benzo(b) furan-2-yl)-3,6-dihydro-2H-pyridin-1-yl,
4-(indol-2-yl)-3,6-dihydro-2H-pyridin-1-yl,
4-(1,4-benzodioxan-6-yl)piperidino,
4-(2,3-dihydrobenzo(b)furan-5-yl)piperidino,
4-(benzo(b)furan-5-yl)piperidino,
4-(chroman-6-yl)piperidino,
4-(2,3-dihydrobenzo(b)furan-5-yl)piperidino,
4-(2,3-dihydrobenzo(b)furan-6-yl)piperidino,
4-(2,3-dihydrobenzo(b)thiophen-5-yl)piperidino,
4-(2,3-dihydrobenzo(b)thiophen-6-yl)piperidino,
4-(benzo(b)furan-5-yl)piperidino,
4-(benzo(b)furan-6-yl)piperidino,
4-(benzo(b)thiophen-5-yl)piperidino,
4-(benzo(b)thiophen-6-yl)piperidino,
4-(4-methoxy-3-methylphenyl)piperidino,
4-(indan-5-yl)piperidino,
4-(inden-5-yl)piperidino,
4-(1H-indolin-5-yl)piperidino,
4-(1-methylindolin-5-yl)piperidino,
1,3-dihydrobenzo(c)furan-1-spiro-4xe2x80x2-piperidin-1xe2x80x2-yl,
4-(chroman-7-yl)piperidino,
4-(2H-chromen-6-yl)piperidino,
4-(3-chloro-4-methoxyphenyl)piperidino,
4-(4-chloro-3-methoxyphenyl)piperidino,
4-(3-chloro-4-methylphenyl)piperidino,
4-(4-chloro-3-methylphenyl)piperidino,
4-(3-chloro-4-fluorophenyl)piperidino,
4-(4-chloro-3-fluorophenyl)piperidino,
4-(3-chloro-4-trifluoromethylphenyl)piperidino,
4-(4-chloro-3-trifluoromethylphenyl)piperidino,
4-(1H-indol-6-yl)piperidino,
4-(1-methylindol-6-yl)piperidino,
4-(1,3-dihydrobenzo(c)furan-5-yl)piperidino,
4-(3,4-dihydro-1H-benzo(c)oxin-6-yl)piperidino,
4-(3,4-dihydro-2H-benzo(b)thiin-6-yl)piperidino,
4-(3,4-dihydro-2H-benzo(b)thiin-7-yl)piperidino,
4-(2-methyl-2,3-dihydrobenzo(b)furan-5-yl)piperidino,
4-(2,2-dimethyl-2,3-dihydrobenzo(b)furan-5-yl)piperidino,
4-(1-methyl-2-oxoindolin-5-yl) piperidino,
4-(4-chloro-2,2-dimethyl-2,3-dihydrobenzo(b)furan-5-yl)piperidino,
4-(7-chloro-2,2-dimethyl-2,3-dihydrobenzo(b)furan-5-yl)piperidino,
4-(2,2-dimethyl-4-methyl-2,3-dihydrobenzo(b)furan-5-yl)piperidino,
4-(2,2-dimethyl-7-methyl-2,3-dihydrobenzo(b)furan-5-yl)piperidino,
4-(2,4,6-trimethylphenyl)piperidino,
4-(2H-1-oxoisoindolin-5-yl)piperidino,
4-(2-methyl-1-oxoisoindolin-5-yl)piperidino,
4-(quinolin-6-yl)piperidino,
4-(isoquinolin-6-yl)piperidino,
4-(4,5-dimethylthiophen-2-yl)piperidino,
4-(4,5-dichlorothiophen-2-yl)piperidino,
4-(4,5-dimethylfuran-2-yl)piperidino,
4-(4,5-dichlorofuran-2-yl)piperidino,
4-(2-methylpyridin-4-yl)piperidino and the like.
As R1, preferred are
1-benzylpiperidin-4-ylamino,
4-phenylcyclohexyl-1-ylamino,
4-hydroxy-4-(4-chlorophenyl)piperidino,
4-hydroxy-4-(2-naphthyl)piperidino,
4-hydroxy-4-(benzo(b)thiophen-2-yl)piperidino,
4-benzylpiperidino,
4-(4-fluorobenzyl)piperidino,
4-(4-chlorobenzyl)piperidino,
4-(4-bromobenzyl)piperidino,
4-phenylpiperidino,
4-(4-fluorophenyl)piperidino,
4-(4-chlorophenyl)piperidino,
4-(4-bromophenyl)piperidino,
4-(4-methoxyphenyl)piperidino,
4-(4-methylphenyl)piperidino,
4-(4-trifluoromethylphenyl)piperidino,
4-(3-chlorophenyl)piperidino,
4-(3-fluorophenyl)piperidino,
4-(3-trifluoromethylphenyl)piperidino,
4-(3-bromophenyl)piperidino,
4-(3-methoxyphenyl)piperidino,
4-(3-methylphenyl)piperidino,
4-(2-fluorophenyl)piperidino,
4-(2-chlorophenyl)piperidino,
4-(2-bromophenyl)piperidino,
4-(2-methylphenyl)piperidino,
4-(2-methoxyphenyl)piperidino,
4-(3,4-dichlorophenyl)piperidino,
4-(3,4-dimethylphenyl)piperidino,
4-(3,4-dimethoxyphenyl)piperidino,
4-(3,4-methylenedioxyphenyl)piperidino,
4-(2,3-dimethoxyphenyl)piperidino,
4-(2,3-dimethylphenyl)piperidino,
4-(2,3-dichlorophenyl)piperidino,
4-(3,5-dimethoxyphenyl)piperidino,
4-(3,5-dimethylphenyl)piperidino,
4-(3,5-dichlorophenyl)piperidino,
4-(2,6-dimethoxyphenyl)piperidino,
4-(3,4,5-trimethoxyphenyl)piperidino,
4-(naphthalen-1-yl)piperidino,
4-(naphthalen-2-yl)piperidino,
4-(6-methoxynaphthalen-2-yl)piperidino,
4-(benzo(b)thiophen-2-yl)piperidino,
4-(benzo(b) furan-2-yl)piperidino,
4-(indol-2-yl)piperidino,
4-(4-fluorobenzyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(4-chlorobenzyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(4-bromobenzyl)-3,6-dihydro-2H-pyridin-1-yl,
4-phenyl-3,6-dihydro-2H-pyridin-1-yl,
4-(4-fluorophenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(4-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(4-bromophenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(4-methoxyphenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(4-methylphenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(4-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(3-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(3-fluorophenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(3-bromophenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(3-methoxyphenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(3-methylphenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(2-fluorophenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(2-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(2-bromophenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(2-methylphenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(2-methoxyphenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(3,4-dichlorophenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(3,4-dimethylphenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(3,4-dimethoxyphenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(3,4-methylenedioxyphenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(2,3-dimethoxyphenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(2,3-dimethylphenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(2,3-dichlorophenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(3,5-dimethoxyphenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(3,5-dimethylphenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(3,5-dichlorophenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(2,6-dimethoxyphenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(3,4,5-trimethoxyphenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(naphthalen-1-yl)-3,6-dihydro-2H-pyridin-1-yl,
4-(naphthalen-2-yl)-3,6-dihydro-2H-pyridin-1-yl,
4-(6-methoxynaphthalen-2-yl)-3,6-dihydro-2H-pyridin-1-yl,
4-(benzo(b)thiophen-2-yl)-3,6-dihydro-2H-pyridin-1-yl,
4-(benzo(b)furan-2-yl)-3,6-dihydro-2H-pyridin-1-yl,
4-(indol-2-yl)-3,6-dihydro-2H-pyridin-1-yl,
4-(1,4-benzodioxan-6-yl)piperidino,
4-(2,3-dihydrobenzo(b)furan-5-yl)piperidino,
4-(benzo(b)furan-5-yl)piperidino,
4-(chroman-6-yl)piperidino,
4-(2,3-dihydrobenzo(b)furan-5-yl)piperidino,
4-(benzo(b)furan-5-yl)piperidino,
4-(2,2-dimethyl-2,3-dihydrobenzo(b)furan-5-yl)piperidino,
4-(7-chloro-2,2-dimethyl-2,3-dihydrobenzo(b)furan-5-yl)piperidino,
4-(2,2-dimethyl-4-methyl-2,3-dihydrobenzo(b)furan-5-yl) piperidino,
4-(2,2-dimethyl-7-methyl-2,3-dihydrobenzo(b)furan-5-yl)piperidino,
4-(2,4,6-trimethylphenyl)piperidino,
4-(2H-1-oxoisoindolin-5-yl)piperidino,
4-(2-methyl-1-oxoisoindolin-5-yl)piperidino,
4-(quinolin-6-yl)piperidino,
4-(isoquinolin-6-yl)piperidino,
4-(4,5-dimethylthiophen-2-yl)piperidino,
4-(4,5-dichlorothiophen-2-yl)piperidino,
4-(4,5-dimethylfuran-2-yl)piperidino,
4-(4,5-dichlorofuran-2-yl)piperidino,
4-(2-methylpyridin-4-yl)piperidino and the like.
As R1, more preferred are
4-(3,4-dimethylphenyl)piperidin-1-yl,
4-(1-naphthyl)piperidin-1-yl,
4-(2-naphthyl)piperidin-1-yl,
4-(6-methoxynaphthalen-2-yl)piperidin-1-yl,
4-(3,4-dimethylphenyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(-naphthyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(2-naphthyl)-3,6-dihydro-2H-pyridin-1-yl,
4-(6-methoxynaphthalen-2-yl)-3,6-dihydro-2H-pyridin-1-yl,
4-(benzo(b)furan-5-yl)piperidino,
4-(2,3-dihydrobenzo(b)furan-5-yl)piperidino,
4-(2,2-dimethyl-2,3-dihydrobenzo(b)furan-5-yl)piperidino,
4-(4-chloro-3-fluorophenyl)piperidino,
4-(4-chloro-3-methylphenyl)piperidino,
4-(3,4-dichlorophenyl)piperidino
and the like.
As R1,
4-(naphthalen-1-yl)piperidino,
4-(naphthalen-2-yl)piperidino,
4-(naphthalen-1-yl)-3,6-dihydro-2H-pyridin-1-yl,
4-(naphthalen-2-yl)-3,6-dihydro-2H-pyridin-1-yl,
4-(3,4-dichlorophenyl)piperidino,
4-(4-chloro-3-methylphenyl)piperidino,
4-(2,2-dimethyl-2,3-dihydrobenzo(b)furan-5-yl)piperidino
and the like are particularly preferable.
As R3, hydrogen atom and C1-C4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl etc.) are preferable and hydrogen atom is particularly preferable.
W is preferably void.
As R7, a group of the following formula is preferable: 
wherein
R8 is hydrogen atom, phenyl group, C1-C4 alkyl group, C1-C2 halogenated alkyl group, halogen atom, C2-C4 alkenyl group, C1-C4 hydroxyalkyl group, alkoxyalkyl group, alkyloxycarbonyl group, optionally substituted amino group, acetamido group, carboxyl group, acyl group, optionally substituted alkyloxy group, alkylthio group or cyano group, and
is R9 is a group of the following formula 
xe2x80x83wherein R10 and R11 are each independently hydrogen atom, C1-C18 alkyl group, optionally substituted aryl group, optionally substituted aralkyl group or alkoxy group, and R12 is hydrogen atom, optionally substituted aryl group, C1-C18 alkyl group, C1-C8 alkoxy group or acyl group.
Ra, Rb and Rc are each specifically hydrogen atom, fluorine atom, chlorine atom, bromine atom, methyl, ethyl, methoxy, methylenedioxy, hydroxy, acetyl and the like, with preference given to all Ra, Rb, Rc being hydrogen atom.
Examples of the group of the following formula 
include groups derived from xcex2-propiolactone, xcex3-butyrolactone, 5,5,-dimethyl-xcex3-butyrolactone, xcex3-valerolactone, xcex4-valerolactone, 6,6-dimethyl-xcex4-valerolactone, xcex3-caprolactone, xcex5-caprolactone, 6,6-dimethyl-xcex5-caprolactone, 2-azetidinone, 2-pyrrolidinone, xcex4-valerolactam, xcex5-caprolactam, hydantoin, 3,5-dihydroimidazol-4-one and the like.
A preferable group of the following formula 
includes the groups of the following formulas 
which are specifically groups derived from xcex3-butyrolactone, xcex4-valerolactone, 2-pyrrolidinone and the like, with particular preference given to a group of the following formula 
Specific examples are groups derived from xcex3-butyrolactone and xcex4-valerolactone.
Preferable embodiment of the formula (I) includes the compounds of the following formulas: 
The phenoxypropylamine compound of the present invention is a compound of the following formula (I) 
wherein each symbol is as defined above.
The preferable compound of the above-mentioned formula (I) is a compound (compound A) wherein each symbol of the formula (I) is as follows:
a bond represented by a solid line and a dotted line shows a double bond;
X is a hydrogen atom, a hydroxy group, a C1-C8 alkoxy group, an acyloxy group or an oxo group;
R1 is a group of the following formula 
xe2x80x83wherein
Y is O or S,
m and n are each independently 0, 1 or 2,
Ar is optionally substituted benzene or naphthalene,
R2 is optionally substituted aryl group or optionally substituted aromatic heterocyclic group,
R5 is optionally substituted aryl group or optionally substituted aromatic heterocyclic group,
Z is void or xe2x80x94CH2xe2x80x94, and
R6 is hydrogen atom, hydroxy group, acetamido group, carboxyl group, alkoxycarbonyl group, cyano group or C1-C8 alkoxy group;
R3 is a hydrogen atom, a C1-C18 alkyl group or a halogen atom;
V is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or the formula xe2x80x94N(R4)xe2x80x94
wherein R4 is hydrogen atom, C1-C18 alkyl group or optionally substituted aralkyl group;
W is void or xe2x80x94CH2xe2x80x94 or xe2x80x94C(xe2x95x90O)""; or
V and W are each a hydrogen atom without bonding;
R7 is a C1-C4 hydroxyalkyl group, an acyl group, an optionally substituted saturated or unsaturated heterocyclic group, an optionally substituted fused heterocyclic group, a C1-C4 alkylsulfonyl group or the formula xe2x80x94Qxe2x80x94R9 
wherein
Q is xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90S)xe2x80x94, xe2x80x94CH2xe2x80x94 or S(xe2x95x90O)2xe2x80x94, and
R9 is a group of the following formula 
xe2x80x83or xe2x80x94NHxe2x80x94NHxe2x80x94R15 
wherein R10 and R11 are each independently hydrogen atom, C1-C18 alkyl group, optionally substituted aryl group, optionally substituted aralkyl group or alkoxy group, R12 is hydrogen atom, optionally substituted aryl group, C1-C18 alkyl group, C1-C8 alkoxy group or acyl group, and R15 is hydrogen atom, phenyl group, C1-C4 alkyl group, C1-C2 halogenated alkyl group, halogen atom, C2-C4 alkenyl group, C1-C4 hydroxyalkyl group, alkoxyalkyl group, alkyloxycarbonyl group, optionally substituted amino group, acetamido group, carboxyl group, acyl group, optionally substituted alkyloxy group, alkylthio group or cyano group; and
Ra, Rb and Rc are each independently a hydrogen atom, a C1-C18 alkyl group, a hydroxy group, a C1-C8 alkoxy group, a halogen atom, an acyl group, a nitro group or an amino group;
provided that when V and W are not directly bonded and V and W are both hydrogen atoms, R7 should not be a group of the formula xe2x80x94COxe2x80x94R9 wherein R9 is as defined above.
In the above-mentioned compound A, a compound A wherein each symbol of the formula (I) is as follows is more preferable:
a bond represented by a solid line or a dotted line shows a double bond;
X is a hydroxy group;
R1 is a group of the following formula 
xe2x80x83wherein
R5 is optionally substituted phenyl group or naphthyl group,
Z is void, and
R6 is hydrogen atom;
R3 is a hydrogen atom or C1-C4 alkyl group;
V is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or the formula xe2x80x94N(R4)xe2x80x94
wherein R4 is hydrogen atom, C1-C6 alkyl group or optionally substituted aralkyl group;
W is void; or
R7 is a group of the following formula 
xe2x80x83or the formula xe2x80x94COxe2x80x94R9 
wherein
R8 is hydrogen atom, phenyl group, C1-C4 alkyl group, C1-C2 halogenated alkyl group, halogen atom, C2-C4 alkenyl group, C1-C4 hydroxyalkyl group, alkoxyalkyl group, alkyloxycarbonyl group, optionally substituted amino group, acetamido group, carboxyl group, acyl group, optionally substituted alkyloxy group, alkylthio group or cyano group, and
R9 is a group of the following formula 
xe2x80x83wherein R10 and R11 are each independently hydrogen atom, C1-C18 alkyl group, optionally substituted aryl group, optionally substituted aralkyl group or alkoxy group, and R12 is hydrogen atom, optionally substituted aryl group, C1-C18 alkyl group, C1-C8 alkoxy group or acyl group; and
Ra, Rb and Rc are each a hydrogen atom.
In the above-mentioned compound A, that having the following formula (Ixe2x80x2) is more preferable: 
wherein each symbol is as defined for compound A.
Specific examples of the above-mentioned compound A are:
(1) 1-(4-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)-propyloxy) benzo (b) furan-2-ylcarbonyl) pyrrolidine,
(2) 4-(4-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)-propyloxy) benzo (b) furan-2-ylcarbonyl)morpholine,
(4) 4-(2-hydroxy-3-(4-(naphthalen-2-yl) piperidino)propyloxy)-N,N-dimethylbenzo (b) furan-2-carboxamide,
(12) 1-(4-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)-propyloxy)benzo(b)thiophen-2-ylcarbonyl)pyrrolidine,
(13) 4-(4-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)-propyloxy)benzo(b)thiophen-2-ylcarbonyl)morpholine,
(15) 4-(2-hydroxy-3-(4-(naphthalen-1-yl)piperidino)propyloxy)-N,N-dimethylbenzo(b)thiophene-2-carboxamide,
(17) 4-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)propyloxy)-N,N-dimethylbenzo(b)thiophene-2-carboxamide,
(20) 4-(7-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)-propyloxy)benzo(b)furan-2-ylcarbonyl)morpholine,
(21) 7-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)propyloxy)-N,N-dimethylbenzo(b)furan-2-carboxamide,
(27) 4-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)propyloxy)-N,N-dimethyl-1H-indole-2-carboxamide,
(30) 4-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)propyloxy)-N,N-dimethyl-1-methylindole-2-carboxamide,
(35) 1-(2-(5-methyl-1,2,4-oxadiazol-3-yl)benzo(b)furan-4-yloxy)-3-(4-(naphthalen-2-yl)piperidino)-2-propanol,
(37) 1-(2-(5-methyl-1,3,4-oxadiazol-2-yl)benzo(b)furan-4-yloxy)-3-(4-(naphthalen-2-yl)piperidino)-2-propanol,
(38) 1-(2-(5-trifluoromethyl-1,3,4-oxadiazol-2-yl)benzo(b)-furan-4-yloxy)-3-(4-(naphthalen-2-yl)piperidino)-2-propanol,
(39) 1-(2-(5-methyl-1,3,4-oxadiazol-2-yl)benzo(b)furan-7-yloxy)-3-(4-(naphthalen-2-yl)piperidino)-2-propanol,
(42) 1-(2-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-indol-4-yloxy)-3-(4-(naphthalen-2-yl)piperidino)-2-propanol,
(44) 1-(2-(3-methyl-1,2,4-oxadiazol-5-yl)benzo(b)furan-4-yloxy)-3-(4-(naphthalen-2-yl)piperidino)-2-propanol,
(48) 1-(2-(5-methyloxazol-2-yl)benzo(b)furan-7-yloxy)-3-(4-(naphthalen-2-yl)piperidino)-2-propanol,
(81) 3-(4-(3,4-dichlorophenyl)piperidino)-1-(2-(5-methyloxazol-2-yl)benzo(b)furan-4-yloxy)-2-propanol,
(88) 1-(4-(3,4-dichlorophenyl)piperidino)-3-(2-(5-methyl-1,3,4-oxadiazol-2-yl)benzo(b)furan-4-yloxy)-2-propanol, and
(93) 3-(4-(3,4-dimethylphenyl)piperidino)-1-(2-(5-ethyl-1,3,4-oxadiazol-2-yl)benzo(b)furan-4-yloxy)-2-propanol, wherein the number in the parenthesis affixed to each compound is an Example number.
The preferable compound of the above-mentioned formula (I) also includes a compound (compound B) wherein each symbol of the formula (I) is as follows:
a bond represented by a solid line and a dotted line shows a double bond or a single bond;
X is a hydrogen atom, a hydroxy group, a C1-C8 alkoxy group or an acyloxy group;
R1 is a group of the following formula 
xe2x80x83wherein
m and n are each independently 0, 1 or 2,
Ar is optionally substituted aromatic hydrocarbon,
R2 is optionally substituted aryl group or optionally substituted aromatic heterocyclic group,
R5 is optionally substituted aryl group or optionally substituted aromatic heterocyclic group,
Z is void or xe2x80x94CH2xe2x80x94,
R6 is hydrogen atom, hydroxy group or C1-C8 alkoxy group and
Yxe2x80x2 is optionally substituted C3-C8 cycloalkylene group, C1-C4 alkyleneoxy group or C1-C8 alkylene group;
R3 is a hydrogen atom, C1-C18 alkyl group or halogen atom;
R7 and W are bonded to form the following formula 
xe2x80x83wherein
E is an oxygen atom or a sulfur atom;
Qxe2x80x2 is optionally substituted 4 to 7-membered heterocycle having 1 or 2 hetero atom(s) selected from the group consisting of nitrogen atom and oxygen atom in the ring, and V is hydrogen atom; and
Ra, Rb and Rc are each independently a hydrogen atom, a C1-C18 alkyl group, a hydroxy group, a C1-C8 alkoxy group, a halogen atom, an acyl group, a nitro group or an amino group.
In the above-mentioned compound B, that wherein each symbol is as follows is more preferable:
a group of the following formula 
xe2x80x83is a group of the following formula 
xe2x80x83wherein
E is an oxygen atom or a sulfur atom,
q is 0, 1, 2 or 3,
R4xe2x80x2, R7xe2x80x2 and R8xe2x80x2 are each independently a hydrogen atom, a C1-C18 alkyl group, an optionally substituted aryl group or an optionally substituted aralkyl group, and
other symbols are as defined in the aforementioned compound B.
In the above-mentioned compound B, that wherein each symbol is as follows is more preferable:
a bond represented by a solid line and a dotted line shows a double bond;
X is a hydroxy group;
R1 is a group of the following formula: 
xe2x80x83wherein
R5 is optionally substituted phenyl group or naphthyl group,
Z is void, and
R6 is hydrogen atom;
R3 is a hydrogen atom or C1-C4 alkyl group; a group of the formula 
xe2x80x83is a group of the following formula 
xe2x80x83wherein q is 1 and R4xe2x80x2 is hydrogen atom or C1-C4 alkyl group); and
Ra, Rb and Rc are each a hydrogen atom.
In the above-mentioned compound B, that having the following formula (Ixe2x80x3) is particularly preferable: 
wherein each symbol is as defined for compound B.
Specific examples of the above-mentioned compound B are as follows:
(306) 5-(2xe2x80x2-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)-propyloxy)benzylidene)-1,3-dimethylimidazolidine-2,4-dione,
(307) xcex1-(2xe2x80x2-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)-propyloxy)benzylidene)-xcex3-butyrolactone,
(308) xcex1-(2xe2x80x2-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)-propyloxy)benzylidene)-xcex3-butyrolactone,
(309) xcex1-(2xe2x80x2-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)-propyloxy)benzylidene)-xcex3-butyrolactone,
(310) xcex1-(2xe2x80x2-(3-(4-(3-fluoro-4-methylphenyl)piperidino)-2-hydroxypropyloxy) benzylidene)-xcex3-butyrolactone,
(311) xcex1-(2xe2x80x2-(3-(4-(3,4-dimethylphenyl)piperidino)-2-hydroxypropyloxy) benzylidene)-xcex3-butyrolactone,
(312) xcex1-(2xe2x80x2-(3-(4-(4-chloro-3-fluorophenyl)piperidino)-2-hydroxypropyloxy) benzylidene)-xcex3-butyrolactone,
(313) xcex1-(2xe2x80x2-(3-(4-(4-chloro-3-trifluoromethylphenyl)-piperidino)-2-hydroxypropyloxy) benzylidene)-xcex3-butyrolactone,
(314) xcex1-(2xe2x80x2-(2-hydroxy-3-(4-(naphthalen-1-yl)piperidino)-propyloxy)benzylidene)-xcex3-butyrolactone,
(315) xcex1-(2xe2x80x2-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)-propyloxy)benzylidene)-6-valerolactone,
(316) xcex1-(2xe2x80x2-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)-propyloxy)benzylidene)-xcex3-valerolactone,
(319) 3-(2xe2x80x2-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)-propyloxy)benzylidene)-2-pyrrolidone,
(322) 3-(2xe2x80x2-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)-propyloxy)benzylidene)-1-methyl-2-pyrrolidone, and
(325) xcex1-(2xe2x80x2-(2-hydroxy-3-(4-(6-methoxynaphthalen-2-yl)piperidino)propyloxy)benzylidene)-xcex3-butyrolactone, wherein the number in the parenthesis affixed to each compound is an Example number.
A synthetic intermediate of compound A may be a compound of the following formula (II) 
wherein each symbol in the formula is as defined below:
X is a hydrogen atom, a hydroxy group, a C1-C8 alkoxy group or an acyloxy group or an oxo group;
R1 is a group of the following formula 
xe2x80x83wherein
Y is O or S,
m and n are each independently 0, 1 or 2,
Ar is optionally substituted benzene or naphthalene,
R2 is optionally substituted aryl group or optionally substituted aromatic heterocyclic group,
R5 is optionally substituted aryl group or optionally substituted aromatic heterocyclic group,
Z is void or xe2x80x94CH2xe2x80x94, and
R6 is hydrogen atom, hydroxy group, acetamido group, carboxyl group, alkoxycarbonyl group, cyano group or C1-C8 alkoxy group;
R3 is a hydrogen atom, a C1-C18 alkyl group or a halogen atom;
V is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or the formula xe2x80x94N(R4)xe2x80x94
wherein
R4 is hydrogen atom, C1-C18 alkyl group or optionally substituted aralkyl group;
W is void, xe2x80x94CH2xe2x80x94 or xe2x80x94C(xe2x95x90O)xe2x80x94; or
V and W are each a hydrogen atom without bonding;
R14 is a hydrogen atom or a C1-C4 alkyl; and
Ra, Rb and Rc are each independently a hydrogen atom, a C1-C18 alkyl group, a hydroxy group, a C1-C8 alkoxy group, a halogen atom, an acyl group, a nitro group or an amino group.
A synthetic intermediate of compound B may be a compound of the following formula (III) 
wherein each symbol in the formula is as defined below:
R is a hydrogen atom, a C1-C4 alkyl group, an allyl group or a 2,3-epoxypropan-1-yl group;
a bond represented by a solid line and a dotted line shows a double bond or a single bond;
E is an oxygen atom or a sulfur atom;
R3 is a hydrogen atom, a C1-C18 alkyl group or a halogen atom;
Qxe2x80x2 is an optionally substituted 4 to 7-membered heterocycle having 1 or 2 hetero atom(s) selected from the group consisting of nitrogen atom and oxygen atom in the ring; and
Ra, Rb and Rc are each independently a hydrogen atom, a C1-C18 alkyl group, a hydroxy group, a C1-C8 alkoxy group, a halogen atom, acyl group, a nitro group or an amino group.
As a synthetic intermediate for the above-mentioned compound B, a compound of the formula (III) wherein each symbol is as defined below is preferable:
the group of the following formula 
xe2x80x83is a group of the following formula 
xe2x80x83wherein
E is an oxygen atom or a sulfur atom,
q is 0, 1, 2 or 3, and
R4xe2x80x2, R7xe2x80x2 and R8xe2x80x2 are each independently hydrogen atom, C1-C18 alkyl group, optionally substituted aryl group or optionally substituted aralkyl group, and
other symbols are as defined with regard to the formula (III).
The pharmaceutically acceptable salts of compounds of the formulas (I), (II) and (III) include acid addition salts with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid etc.) or organic acids (e.g., acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, ascorbic acid, terephthalic acid, adipic acid etc.).
The compounds of the formulas (I), (II) and (III) and pharmaceutically acceptable salts thereof may be present in the form of a hydrate or a solvate. These hydrates and solvates are also encompassed in the present invention. When the compound of the formula (I) has an asymmetric atom, at least two kinds of optical isomers exist. The optical isomers and racemates thereof are encompassed in the present invention.
The compound of the formula (I) can be synthesized by the following methods. Each symbol in the following reaction formulas is as defined above, unless particularly specified.
The compound of the formula (I) and synthetic intermediates of the formulas (II) and (III) can be produced according to the following reaction formulas A""Z and Qxe2x80x2xe2x80x94Txe2x80x2, as well as methods analogous to the following examples and the like. In the formulas, the symbol A refers to a leaving group (or nucleofugal group) well known in the organic synthesis, such as chlorine atom, bromine atom, iodine atom, mesylate, tosylate, nosylate, triflate and the like. Leaving groups (or nucleofugal groups) are well known to those of ordinary skill in the art of organic syntheses. 
Reaction formula A: A method comprising reacting a phenol derivative 1 and 2,3-epoxypropane compound 2 having a leaving group (or nucleofugal group) at 1-position, followed by reaction with Hxe2x80x94R1,
Reaction formula B: A method comprising reacting Hxe2x80x94R1 and 2,3-epoxypropane compound 2 having a leaving group (or nucleofugal group) at 1-position to give compound 4, which is reacted with a phenol derivative 1,
Reaction formula C: A method comprising reacting a phenol derivative 1 and 2-propanone 5 having leaving groups (or nucleofugal groups) at 1,3-position to give compound 6, which is reacted with Hxe2x80x94R1 to give a product 7, followed by reduction thereof,
Reaction formula D: A method comprising reacting Hxe2x80x94R1 and 2-propanone compound 5 having leaving groups (or nucleofugal groups) at 1,3-position to give compound 8, which is reacted with phenol derivative 1 to give a product 7, followed by reduction thereof,
Reaction formula E: A method comprising reacting phenol derivative 1 and allyl compound 9 (e.g., 3-allyl bromide etc.) having a leaving group (or nucleofugal group) at 3-position to give a product 10, which is epoxidated and successively reacted with Hxe2x80x94R1, and the like. The methods for synthesis of the compound of the formula (I) are not limited to those mentioned above.
Particularly, the optically active compound of the formula (I) (Xxe2x95x90OH) can be synthesized by the following reaction formulas Fxe2x80x94L and the like. In these reaction formulas, the symbol R* means a part other than carboxyl group of optically active carboxylic acid. 
Reaction formula F: A method comprising asymmetric epoxydation of intermediate 10 obtained by the above-mentioned reaction formula E, using optically active base and asymmetric ligand in catalytic or stoichiometric amounts to give optically active intermediate 3, which is reacted with Hxe2x80x94R1,
Reaction formula G: A method comprising reacting phenol derivative 1 and optically active 2,3-epoxypropane derivative 2 having a leaving group (or nucleofugal group) at 1-position to give compound 3, which is reacted with Hxe2x80x94R1,
Reaction formula H: A method comprising reacting Hxe2x80x94R1 and optically active 2,3-epoxypropane derivative 2 having a leaving group (or nucleofugal group) at 1-position to give compound 4, which is reacted with phenol derivative 1,
Reaction formula I: A method comprising condensing a racemic mixture of the compound of the formula (I) with optically active carboxylic acid 11 to convert the compound to optically active ester 12, which is followed by crystallization, column chromatography and the like to resolve the compound into two diastereomers,
Reaction formula J: A method comprising asymmetric reduction of intermediate 7 obtained by the above-mentioned reaction formulas C and D, using a chiral ligand,
Reaction formula K: A method comprising forming a salt in a racemic mixture of the compound of the formula (I) and optically active carboxylic acid 11, whereby both isomers are resolved based on difference in crystallinity,
Reaction formula L: A method comprising condensing a racemic mixture of the compound of the formula (I) with carboxylic acid 13 to once convert the compound to an ester, and hydrolyzing the ester enantioselectively using an enzyme.
The methods for synthesizing the optically active compound of the formula (I) (Xxe2x95x90OH) are not limited to those mentioned above.
A compound of the formula (I) wherein X is hydrogen atom can be synthesized as in the following reaction formulas Mxe2x80x94N and the like. 
Reaction formula M: A method comprising reacting phenol derivative 1 and propane derivative 15 having leaving groups or nucleofugal groups at 1,3-positions to synthesize intermediate 16, and condensing the intermediate 16 and Hxe2x80x94R1 in the presence of deoxidizing agent,
Reaction formula N: A method comprising reacting Hxe2x80x94R1 and propane derivative 15 having leaving groups or nucleofugal groups at 1,3-positions to synthesize intermediate 17 and condensing the intermediate 17 and phenol derivative 1 in the presence of deoxidizing agent.
Of the compounds of the formula (I), a compound wherein X is alkoxy can be derived from the compound of the formula (I) wherein X is OH as in the following reaction formula 0 wherein R13 is alkyl group. 
Reaction formula O: A method comprising alkylating hydroxy group of a compound of the formula (I) wherein X is hydroxy group, in the presence of deoxidizing agent.
Of the compounds of the formula (I), a compound wherein R7 is the formula: xe2x80x94Qxe2x80x94R9 wherein Q is xe2x80x94C(xe2x95x90O)xe2x80x94 or xe2x80x94CH2xe2x80x94 can be derived from carboxylic acid derivative 18, as in the following the reaction formula P. 
Reaction formula P: A method comprising condensing carboxylic acid derivative 18 with Hxe2x80x94R9 in the presence of amidating agent to synthesize amide compound (Qxe2x95x90CO), and reducing the amide compound to synthesize amino compound (Qxe2x95x90CH2). The amidating agent to be used for this method is exemplified by dicyclohexylcarbodiimide (DCC), diethyl cyanophosphate, diphenylphosphoryl azide (DPPA), 1,1xe2x80x2-carbonylbis-1H-imidazole (CDI), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) and the like. The reducing agent to be used for the reduction is exemplified by lithium aluminum hydride, diisopropyl aluminum hydride, diborane, sodium borohydride and the like.
Of the phenol derivatives 1 used in Reaction formulas A, B, D, E, G, H, M and N, a compound wherein R7 is the formula: xe2x80x94Qxe2x80x94R9 can be synthesized according to the following reaction formulas Q-S and the like. In these reaction formulas, the symbol PG means a protecting group (e.g., methyl, ethyl, methoxymethyl, ethoxymethyl, trimethylsilyl, benzyl, acetyl, benzoyl etc.) that can be eliminated easily in the organic synthesis. 
Reaction formula Q: A production method comprising condensing carboxylic acid derivative 19 with Hxe2x80x94R9, using amidating agent, and then eliminating the protecting group to give phenol derivative (1, Qxe2x95x90CO). As the amidating agent, dicyclohexylcarbodiimide (DCC), diethyl cyanophosphate, diphenylphosphoryl azide (DPPA), 1,1xe2x80x2-carbonylbis-1H-imidazole (CDI), 1-ethyl-3 -(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) and the like can be used.
Reaction formula R: A production method comprising reducing amide compound 20 with a reducing agent, and eliminating the protecting group to give phenol derivative (1, Qxe2x95x90CH2). As the reducing agent, lithium aluminum hydride, diisopropyl aluminum hydride, diborane, sodium borohydride and the like can be used.
Reaction formula S: A production method comprising condensing, sulfonic chloride derivative 22 with Hxe2x80x94R9 using a deoxidizing agent, and eliminating the protecting group to give phenol derivative (1, Qxe2x95x90SO2).
In the following, the reaction formulas T-Z are shown as typical synthetic methods of representative compounds wherein R7 is optionally substituted heterocycle in the reaction formulas A-H, M and N. In these reaction formulas, the symbol PG is as defined above. 
Reaction formula T: A production method of phenol derivative 1 having a 1,3,4-oxadiazole ring, which method comprises cyclization of diacylhydrazine derivative 24 with a dehydrating agent, and deprotection. The phenol derivative 1 having a 1,3,4-oxadiazole ring can be also synthesized by reacting azo compound and triphenylphosphine, in the presence of a deoxidizing agent, followed by deprotection. As the dehydrating agent, polyphosphoric acid, oxalyl chloride, phosphorus trichloride, sulfuric acid, phosphorus oxychloride, thionyl chloride, oxalyl chloride and the like can be used. As the azo compound, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD) and the like can be used.
Reaction formula U: A production method of phenol derivative 1 having a 1,2,4-oxadiazole ring, which method comprises condensing carboxylic acid derivative 19 and hydroxyimino compound 26 using an amidating agent to give compound 27, which is subjected to cyclization using a dehydrating agent or by heating for dehydration, followed by deprotection. As the dehydrating agent, polyphosphoric acid, phosphorus pentachloride, phosphorus trichloride, sulfuric acid, phosphorus oxychloride, thionyl chloride, oxalyl chloride and the like can be used.
Reaction formula V: A production method of phenol derivative 1 having a 1,2,4-oxadiazole ring, which method comprises condensing nitrile derivative 29 and hydroxylamine to give compound 30, to which acid anhydride 31 is added to allow cyclization by heating for dehydration, followed by deprotection. 
Reaction formula W: A production method of phenol derivative 1 having a 1,3,4-thiadiazole ring, which method comprises conversion of hydrazone compound 33 into thione compound with a sulfidation agent to give compound 34, which is cyclized with compound 35 by heating, followed by deprotection. As the sulfidation agent, Lawesson reagent, diphosphorus pentasulfide and the like can be used.
Reaction formula X: A production method of phenol derivative 1 having a thiazole ring, which method comprises cyclization of compound 37 and thioamide compound 38 by heating, followed by deprotection. 
Reaction formula Y: A production method of phenol derivative 1 having a isoxazole ring, which method comprises cyclization of hydroxyimino compound 40, using a dehydrating agent or by heating for dehydration, followed by deprotection. As the dehydrating agent, polyphosphoric acid, phosphorus pentachloride, phosphorus trichloride, sulfuric acid, phosphorus oxychloride, thionyl chloride, oxalyl chloride and the like can be used.
Reaction formula Z: A production method of phenol derivative 1 having an oxazole ring, which method comprises condensing acid halide compound 42 and acetylene compound 43 to give compound 44, followed by cyclization using mercury(II) acetate and deprotection.
Of the phenol derivatives 1 to be used for the reaction formulas A, B, D, E, G, H, M and N, a compound wherein R and W are bonded to form a ring can be also synthesized by the methods of the following reaction formulas Qxe2x80x2-Txe2x80x2. 
Reaction formula Qxe2x80x2:The phenol derivative 1, which is a benzylidene compound, can be synthesized by reacting phenol derivative 18 and carbonyl (thiocarbonyl) derivative 19 in the presence of a base such as sodium hydride, sodium alcoholate and the like. Further, the phenol derivative 1, which is a benzyl compound, can be synthesized by reducing the obtained phenol derivative 1 (benzylidene compound) in the presence of a catalyst such as palladium carbon and the like.
When R and W are bonded to form a ring, which is a lactam or hydantoin (or their sulfur derivatives), and R7xe2x80x2 is other than hydrogen atom, phenol derivative 1 can be also synthesized by the method of the reaction formula Rxe2x80x2. 
Reaction formula Rxe2x80x2: Synthesis is available by lithiation of a lactam derivative or hydantoin derivative (or their sulfur derivatives) wherein R7xe2x80x2 is other than hydrogen atom, with an organic lithium reagent such as n-BuLi and the like, reacting the same with a phenol derivative 20, wherein hydroxyl group is protected, to once convert to benzyl alcohol compound 21, followed by treatment with an acid. Moreover, by reduction of phenol derivative 1 (benzylidene compound) in the presence of a catalyst such as palladium carbon and the like, phenol derivative 1, which is a benzyl compound, can be synthesized.
The phenol derivative 1 (or its sulfur derivative) containing hydantoin, wherein R7xe2x80x2 and R8xe2x80x2 are the same substituents, can be also synthesized by the method of the reaction formula Sxe2x80x2. 
Reaction formula Sxe2x80x2: The phenol derivative 20, wherein hydroxyl group is protected, is reacted with hydantoin (or its sulfur derivative) along with a base such as sodium hydride, sodium alcoholate and the like to give benzylidene compound 22, followed by deprotection to give phenol derivative 1, wherein R7xe2x80x2 and R8xe2x80x2 are hydrogen atoms. Moreover, by reacting benzylidene compound 22, which is an intermediate, with Wxe2x80x94R7xe2x80x2 having a nucleofugal group to synthesize intermediate 23, and deprotecting the same, the phenol derivative 1 (or its sulfur derivative) containing hydantoin, wherein R7xe2x80x2 and R8xe2x80x2 are the same, can be synthesized.
The phenol derivative 1 (or its sulfur derivative) containing 3,5-dihydroimidazol-4-one can be also synthesized by the method of the reaction formula Txe2x80x2. 
Reaction formula Txe2x80x2: The phenol derivative 20, wherein hydroxyl group is protected, is reacted with glycine derivative 24 to give benzylidene compound 25, which is then reacted with amine R7xe2x80x2xe2x80x94NH2 to give intermediate 26. This intermediate is deprotected to give phenol derivative 1 (or its sulfur derivative) containing 3,5-dihydroimidazol-4-one.
There are many methods for obtaining phenol derivative 1 other than those mentioned above that are known to synthesis chemists, and therefore, the methods for obtaining the compound are not limited to those shown above.
These reactions and applications ultimately leading to the formula (I) of the present invention are well known to those of ordinary skill in the field of organic chemical synthesis. The improvements to adopt the conditions and reagents for the synthesis of specific compounds of the formula (I) inclusive of the inventive compound, beyond those described, are known to synthesis chemists. For more detailed description, respective synthetic examples are shown under Examples.
The compounds of the formula (I) obtained as mentioned above have selective affinity for as well as simultaneous antagonistic activity against 5-HT1A receptors and have a 5-HT reuptake inhibitory action. Therefore, the compounds can provide effective pharmaceutical agents for diseases accompanying serotoninergic neurotransmission functional disorders. They are also effective as 5HT1A antagonists having a selective serotonin reuptake inhibitory action, or as selective serotonin reuptake inhibitors having a 5HT1A antagonistic action.
That is, the inventive compounds show quick expression of the anti-depressive effect and are useful as a so-called rapid onset antidepressant. They are also useful for the treatment of mammals inclusive of human for central nervous system diseases mediated by 5-HT, such as schizophrenia, anxiety neurosis, obsessive-compulsive disorder (OCD), panic disorder, social anxiety disorder, seasonal emotional disorder, Anorexia Nervosa, Bulimia Nervosa, nocturnal enuresis, children""s hyperlocomotion, post-traumatic stress disorder (PTSD), senile dementia, hemicrania, stroke, Alzheimer""s disease, recognition disorder, hypertension, gastrointestinal injury, feeding disorders, premenstrual syndrome (PMS), abnormal body temperature regulation and sexual disorder, pain, as well as abnormal cardiovascular system, drug abuse and the like.
When the compound of the present invention is used as a pharmaceutical agent, a systemic administration of a pharmacologically acceptable amount of the compound of the formula (I) or a pharmacologically acceptable acid addition salt thereof to a mammal is included. The dose requires careful control for each case, and in consideration of the age, body weight and condition of the subject, administration route, as well as nature and severity of disease, the general daily dose in the case of parenteral administration is 0.01-100 mg/kg, preferably 0.1-1 mg/kg, and that in the case of oral administration is 0.5-10 mg/kg, preferably 1-5 mg/kg. The administration method in the present invention includes oral, rectal and parenteral (e.g., intramuscular, intravenous, percutaneous and subcutaneous) administrations.
For anti-depression, the compound of the present invention may be administered as a single therapeutic agent or may be administered as a mixture with other therapeutic agents. For therapy, the compound is generally given as a pharmacological composition containing the compound of the formula (I) or a pharmaceutically acceptable salt thereof in an amount sufficient to show an anti-depressive effect, and a pharmaceutically acceptable carrier. A pharmacological composition containing about 1-500 mg of the active ingredient per unit dose is desirable.
According to a conventional method, it is prepared into tablets, lozenges, capsules, powders, aqueous or oily suspensions, syrups, elixirs, aqueous solutions and the like. The pharmacological composition to be used naturally shows properties that vary depending on the objective administration route. For example, an oral composition may be tablet or capsule, and may contain a conventional excipient such as binder (starch etc.) and moistening agent (sodium laurylsulfate etc.). A solution or suspension of the present invention containing a conventional pharmacological vehicle may be used for parenteral administration, such as an aqueous solution for intravenous injection and oily suspension for intramuscular injection.